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WO2019005588A1 - Modulateurs allostériques de type 3-(1h-pyrazol-4-yl)pyridine du récepteur muscarinique m4 de l'acétylcholine - Google Patents

Modulateurs allostériques de type 3-(1h-pyrazol-4-yl)pyridine du récepteur muscarinique m4 de l'acétylcholine Download PDF

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Publication number
WO2019005588A1
WO2019005588A1 PCT/US2018/038891 US2018038891W WO2019005588A1 WO 2019005588 A1 WO2019005588 A1 WO 2019005588A1 US 2018038891 W US2018038891 W US 2018038891W WO 2019005588 A1 WO2019005588 A1 WO 2019005588A1
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WIPO (PCT)
Prior art keywords
pyrazol
pyridin
methyl
pyridine
carbonitrile
Prior art date
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Ceased
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PCT/US2018/038891
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English (en)
Inventor
John J. Acton, Iii
Jianming Bao
Qiaolin Deng
Melissa Egbertson
Ronald FERGUSON, III
Xiaolei Gao
Scott Timothy HARRISON
Timothy J. Henderson
Sandra L. Knowles
Michael Man-Chu Lo
Robert D. Mazzola, Jr.
Meng NA
Oleg B. Selyutin
Takao Suzuki
Fengqi Zhang
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MSD R&D China Co Ltd
Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
Original Assignee
MSD R&D China Co Ltd
Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
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Application filed by MSD R&D China Co Ltd, Merck Sharp and Dohme Ltd, Merck Sharp and Dohme LLC filed Critical MSD R&D China Co Ltd
Priority to EP18824389.3A priority Critical patent/EP3644991B1/fr
Priority to US16/621,953 priority patent/US11339156B2/en
Publication of WO2019005588A1 publication Critical patent/WO2019005588A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Acetylcholine is a key neurotransmitter that modulates neuronal function in the peripheral nervous system (PNS) and central nervous system (CNS).
  • ACh mediates its actions via two families of receptors, termed the muscarinic ACh receptors (mAChRs) and the nicotinic ACh receptors (nAChRs).
  • mAChRs muscarinic ACh receptors
  • nAChRs nicotinic ACh receptors
  • Alzheimer's disease It has therefore been hypothesized that cholinergic hypofunction contributes to the cognitive deficits of patients suffering from Alzheimer's disease. Consequently,
  • acetylcholinesterase inhibitors which inhibit ACh hydrolysis and potentiate cholinergic signaling have been demonstrated to not only provide improvements in cognitive symptoms associated with Alzheimer's disease, but also show efficacy in treating the psychiatric symptoms.
  • Acetylcholinesterase inhibitors have not been shown to change the underlying disease pathology.
  • Muscarinic acetylcholine receptors are members of the G protein-coupled receptor superfamily which mediate the actions of the neurotransmitter acetylcholine in both the central and peripheral nervous system. Muscarinic acetylcholine receptors are prevalent throughout the body and five distinct muscarinic receptors (M1-M5) have been identified in mammals. The muscarinic receptors are known to contain one or more allosteric sites which may alter the affinity with which muscarinic ligands bind to the primary binding or orthosteric sites.
  • muscarinic receptors are involved in cognitive, behavior, sensory, motor and autonomic functions.
  • the M4 muscarinic acetylcholine receptor is predominantly expressed in the striatum, but also in the hippocampus and cortex.
  • Muscarinic receptors in the central nervous system play a critical role in mediating higher cognitive processing and control of dopamine release.
  • Administration of nonselective muscarinic antagonists can induce cognitive deficits and psychosis in humans suggesting that mAChR activation may provide pro-cognitive and antipsychotic efficacy.
  • mAChR agonists have been developed and entered clinical studies for the treatment of cognitive and psychiatric symptoms associated with Alzheimer's and neuropsychiatric diseases such as schizophrenia. (Carruthers, Neuroscience & Biobehavioral Rev., 2015, 55: 393-402; Jones, et al. Neuropsychopharmacology, 2012, 37: 16-42).
  • M1/M4 preferring mAChR agonist xanomeline was assessed in patients with Alzheimer's disease, and while showing a trend for improving cognitive deficits, did produce robust and dose-dependent reductions in hallucinations, delusions, vocal outbursts, and other behavioral disturbances in these patients.
  • Xanomeline in addition to other mAChR agonists have been demonstrated to produce robust antipsychotic-like effects in a number of preclinical paradigms.
  • xanomeline reverses a number of dopamine driven behaviors, including amphetamine induced locomotion in rats, apomorphine induced climbing in mice, dopamine agonist driven turning in unilateral 6-OH-DA lesioned rats and amphetamine induced motor unrest in monkeys (without EPS liability). It also has been shown to inhibit A10, but not A9, dopamine cell firing and conditioned avoidance and induces c-fos expression in prefrontal cortex and nucleus accumbens, but not in striatum in rats.
  • M4 positive allosteric modulators is a strategy to overcome the challenges of developing selective orthosteric muscarinic agonists. Indeed, studies with M4 PAMs have shown that selective activation of M4 mAChRs can reverse both
  • the compounds of the present invention which are allosteric modulators of the M4 muscarinic acetylcholine receptor, are believed to be useful in the treatment of Alzheimer's disease and other diseases mediated by the muscarinic M4 muscarinic acetylcholine receptor.
  • the present invention is directed to pyrazol-4-yl-pyridine compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor.
  • the present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which M4 muscarinic acetylcholine receptors are involved.
  • the present invention is also directed to compositions comprising these compounds.
  • the present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which M4 muscarinic acetylcholine receptors are involved.
  • the present invention is directed to compounds of the formula I:
  • A is selected from: benzofuranone, benzoimidazole, benzoisoxazole, benzothiazole, benzotriazole, benzoxazole, dihydrobenzofuranone, dihydroisoindole, imidazopyridazine, imidazopyridine, indazole, isobenzofuranone, isoindoline, isoindolinone, oxazolopyridine, pyrazolopyridine, pyrrolopyridinone, and triazolopyridine;
  • R1 is selected from:
  • R4 is selected from:
  • R5 is -Ci-6alkyl, which is unsubstituted or substituted with:
  • each of R8, R9 and RlO is independently selected from:
  • -OCi-6alkyl which is unsubstituted or substituted with a hydroxy, -OCi-6alkyl, cyclopropyl, cyclobutyl, or 1-3 fluoro,
  • pyrrolidinyl, piperidinyl, or piperazinyl is unsubstituted or substituted with hydroxy, methoxy, or 1-3 fluoro, and
  • A, Rl, R5, R8 3 R9 a nd RlO are defined herein; or a pharmaceutically acceptable salt thereof.
  • A, Rl, R5, R8 3 R9 a nd RlO are defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds wherein A is selected from: cinnoline, isoindolinone, phenyl, pyrrolopyridinone, and quinolone.
  • An embodiment of the present invention includes compounds wherein A is quinolone.
  • An embodiment of the present invention includes compounds wherein A is isoindolinone.
  • An embodiment of the present invention includes compounds wherein Rl is hydrogen. An embodiment of the present invention includes compounds wherein Rl is methyl.
  • R2 is selected from:
  • An embodiment of the present invention includes compounds wherein R2 is hydrogen.
  • R3 is selected from:
  • An embodiment of the present invention includes compounds wherein R3 is hydrogen.
  • An embodiment of the present invention includes compounds wherein R4 is hydrogen.
  • An embodiment of the present invention includes compounds wherein R4 is cyano.
  • An embodiment of the present invention includes compounds wherein R4 is fluoro.
  • An embodiment of the present invention includes compounds wherein R5 is -Ci_ 6alkyl, which is unsubstituted or substituted with fluoro.
  • R5 is selected from:
  • R , R9 and RlO is independently selected from:
  • An embodiment of the present invention includes compounds wherein each of R , R9 and RlO is independently selected from:
  • An embodiment of the present invention includes compounds wherein each of R , R9 and RlO is hydrogen.
  • Certain embodiments of the present invention include a compound which is selected from the subject compounds of the Examples herein or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. Likewise, the present invention includes tautomeric forms of the compounds disclosed herein. Formula I shows the structure of the class of compounds without specific stereochemistry.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • Ci-6 as in Ci-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that Ci-6alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl.
  • (CH2-5cycloalkyl-0-) indicates the presence of cyclopropoxy, cyclobutoxy, tetrahydrofuranyl, or tetrahydropyranyl ring.
  • Substituents (such as Rla Rib and Rlc) may be absent if the valency of the group to which they are attached does not permit such substitution.
  • a group which is designated as being independently substituted with substituents may be
  • the present invention also includes all pharmaceutically acceptable isotopic variations of a compound of the Formula I in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Such compounds are identical to those disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2H and 3H, carbon such as HC, 1 C and 14c, nitrogen such as 1 N and 1 N, oxygen such as 1 0, 1 ⁇ 0 and 180, phosphorus such as 32p, sulfur such as 35s, fluorine such as 1 F, iodine such as 1 3i and 125i 5 and chlorine such as 36Q.
  • isotopically-labelled compounds of Formula I for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e.
  • Substitution with positron emitting isotopes can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • An embodiment of the present invention includes compounds that are substituted with a positron emitting isotope.
  • An embodiment of the present invention includes compounds that are substituted with a 1 lC isotope.
  • An embodiment of the present invention includes compounds that are substituted with an 1 F isotope.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of the invention.
  • different isotopic forms of hydrogen (H) include protium (1H) and deuterium ( 2 H).
  • Protium is the isotopic forms of hydrogen (H) include protium (1H) and deuterium ( 2 H).
  • a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non- toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the present invention.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates or solvates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piped dine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particular embodiments include the citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts. Salts of the compounds of the invention may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • M4 muscarinic acetylcholine receptor refers to one of the five subtypes of the muscarinic acetylcholine receptor, which is from the superfamily of G-protein coupled receptors. The family of muscarinic receptors is described, for example, in Pharmacol Ther, 1993, 58:319-379; Eur J Pharmacol, 1996, 295:93-102, and Mol Pharmacol, 2002, 61 : 1297- 1302.
  • the muscarinic receptors are known to contain one or more allosteric sites, which may alter the affinity with which muscarinic ligands bind to the primary binding or orthosteric sites. See, e.g., S. Lazareno, et al., Mol Pharmacol, 2002, 62:6, 1491-1505.
  • the terms "positive allosteric modulator” and “allosteric potentiator” are used interchangeably, and refer to a ligand which interacts with an allosteric site of a receptor to augment the response produced by the endogenous ligand at the orthosteric binding site.
  • the compounds of the invention are allosteric modulators of the M4 muscarinic acetylcholine receptor, including as positive allosteric modulators of the M4 muscarinic acetylcholine receptor and silent allosteric modulators of the M4 muscarinic acetylcholine receptor. Some of the compounds of the invention are agonists of the M4 muscarinic acetylcholine receptor.
  • Some of the compounds of the invention are allosteric modulators of the Ml muscarinic acetylcholine receptor, or may be agonists of the Ml muscarinic acetylcholine receptor.
  • a modulator or potentiator may directly or indirectly augment the response produced by the endogenous ligand (such as acetylcholine or xanomeline) at the orthosteric site of the M4 muscarinic acetylcholine receptor in an animal, in particular, a human.
  • the actions of ligands at allosteric receptor sites may also be understood according to the "allosteric ternary complex model," as known by those skilled in the art.
  • the allosteric ternary complex model is described with respect to the family of muscarinic receptors in Birdsall et al, Life Sciences, 2001, 68:2517-2524.
  • Christopoulos Nature Reviews: Drug Discovery, 2002, 1 : 198-210.
  • the compounds of the invention bind to an allosteric binding site that is distinct from the orthosteric acetylcholine site of the M4 muscarinic acetylcholine receptor, thereby augmenting the response produced by the endogenous ligand acetylcholine at the orthosteric site of the M4 muscarinic acetylcholine receptor. It is also believed that the compounds of the invention bind to an allosteric site which is distinct from the xanomeline site of the M4 muscarinic acetylcholine receptor, thereby augmenting the response produced by the endogenous ligand xanomeline at the orthosteric site of the M4 muscarinic acetylcholine receptor.
  • the present invention is also directed to the use of the compounds disclosed herein as modulators of M4 muscarinic acetylcholine receptor activity.
  • the subject compounds and pharmaceutically acceptable salts thereof are useful in a method of M4 modulating muscarinic acetylcholine receptor activity in a subject such as a mammal comprising the administration of an amount of the compound.
  • a subject such as a mammal comprising the administration of an amount of the compound.
  • a variety of other mammals may be administered with a compound of the present invention.
  • the present invention is directed to a compound of the present invention or a pharmaceutically acceptable salt thereof that could be useful in therapy.
  • the present invention may further be directed to a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for modulating M4 muscarinic acetylcholine receptor activity or treating the disorders and diseases noted herein in humans and animals.
  • a subject administered with a compound of the present invention, or a pharmaceutically acceptable salt thereof, is generally a mammal, such as a human being, male or female.
  • the amount of compound administered to the subject is an amount sufficient to modulate the M4 muscarinic acetylcholine receptor in the subject.
  • the amount of compound can be an "effective amount” or "therapeutically effective amount", wherein the subject compound or pharmaceutical composition is administered in an amount that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, or otherwise inhibiting the noted disease and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • An effective amount does not necessarily include considerations of toxicity and safety related to the
  • treatment and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a subject that is predisposed to such disease or disorder.
  • administering should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to to the subject.
  • dose function refers to abnormality or impairment in the function of the noted system.
  • compositions as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the utility of the compounds in accordance with the present invention as modulators of M4 muscarinic acetylcholine receptors may be readily determined without undue experimentation by methodology well known in the art, including monitoring the mobilization of intracellular Ca++, determining the levels of intracellular cAMP, or quantiting the exchange of GDP for [35S]yGTP.
  • M4 muscarinic acetylcholine receptor modulating activity of the compounds of the present invention was determined in accordance with the following experimental method.
  • CHO-K1 cells stably transfected with human M4 receptor and chimeric G- protein Gaqi5 are thawed from liquid N 2 storage, resuspended in growth medium, plated in black, clear bottom 384 well plates, and incubated 16-20 hours at 37 °C, 5% C0 2 .
  • acetylcholine final concentration calculated to achieve 70% of the maximal acetylcholine response
  • IP inflection point
  • the intrinsic M4 muscarinic acetylcholine receptor modulating activity of a compound which may be used in the present invention may be determined by these assays.
  • the M4 muscarinic acetylcholine receptor has been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species.
  • the compounds of the present invention could therefore potentially have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with M4 muscarinic acetylcholine receptors, including one or more of the following conditions or diseases, and other diseases related to general M4 muscarinic acetylcholine receptor system dysfunction.
  • Potential conditions or disorders for which the compounds of the invention may be useful further include one or more of the following conditions or diseases: Alzheimer's disease (including mild Alzheimer's disease, moderate Alzheimer's disease and severe Alzheimer's disease), olfactory impairment associated with Alzheimer's disease, Down's syndrome, olfactory impairment associated with Down's syndrome, Parkinson's disease, olfactory impairment associated with Parkinson's disease, stroke, microgliosis brain inflammation, pre-senile dementia, senile dementia, progressive supranuclear palsy, cortical basal degeneration, ⁇ -amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, cognitive disorders (including mild cognitive impairment), glaucoma, amyloidosis, type II diabetes, diabetes-associated
  • amyloidogenesis scrapie, bovine spongiform encephalitis, traumatic brain injury, Creutzfeld- Jakob disease, schizophrenia, sleep disorders, pain disorders (including acute pain, inflammatory pain and neuropathic pain), pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, schizophrenia, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism, atherosclerosis, tolerance and/or dependence to opioid treatment of pain, and for treatment of withdrawal syndrome of e.g., alcohol, opioids, and cocaine, Huntington's disease
  • Potential conditions or disorders for which the compounds of the invention may be useful further include one or more of the following conditions or diseases: schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance- induced or drug-induced (phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) psychosispsychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and posttraumatic stress syndrome), including both the positive and the negative symptoms of schizophrenia and other psychoses; cognitive disorders including dementia (associated with Alzheimer's disease,
  • tardive dyskinesias Huntington's disease, Pick's disease, Creutzfeldt- Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age related cognitive decline; delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic break, tardive psychosis, myxedematous psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar I disorder with psychotic features, and substance-induced psychotic disorder; major depressive disorder, affective disorder, bipolar disorder, electrolyte disorder, neurological disorder, hypoglycemia, AIDS, lupus, and post-traumatic stress disorder; brain tumor, dementia with Lewy bodies, multiple sclerosis, sarcoidosis, Lyme disease, syphilis, Alzheimer's disease, Parkinson's disease, and anti-NMDA receptor encephalitis.
  • the present invention provides a method for treating schizophrenia or psychosis comprising administering to a patient in need thereof an effective amount of a compound of the present invention.
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder.
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • the term "schizophrenia or psychosis” includes treatment of those mental disorders as described in DSM-IV-TR.
  • the skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress.
  • the term “schizophrenia or psychosis” is intended to include like disorders that are described in other diagnostic sources.
  • mood disorders such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder, mood disorders due to a general medical condition, and substance-induced mood disorders
  • affective neurosis depressive neurosis
  • anxiety neurosis anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition
  • acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage
  • idiopathic symptoms such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive
  • parkinsonism parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), chronic fatigue syndrome, fatigue, including Parkinson's fatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorder or a circadian rhythm disorder, medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic- induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias [including tremor (such as rest tremor, essential tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug- induced chorea and
  • HIV post-chemotherapy pain
  • post-stroke pain post-operative pain
  • neuralgia emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers; Kallman's syndrome (anosmia); asthma; cancer; conditions associated with visceral pain such as irritable bowel syndrome, and angina; eating disorders; urinary incontinence; substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.); psychosis; schizophrenia; anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder); mood disorders (including depression, mania, bipolar disorders); trigeminal neuralgia; hearing loss; tinnitus;
  • neuronal damage including ocular damage; retinopathy; macular degeneration of the eye; emesis; brain edema; pain, including acute and chronic pain states, severe pain, intractable pain, inflammatory pain, neuropathic pain, post-traumatic pain, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine headache.
  • Potential sleep conditions or disorders for which the compounds of the invention may be useful include enhancing sleep quality; improving sleep quality; augmenting sleep maintenance; increasing the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency or duration of REM sleep bouts; altering the timing, frequency or duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasing the amount and percentage of stage 2 sleep; promoting slow wave sleep; enhancing EEG-delta activity during sleep; increasing daytime alertness; reducing daytime drowsiness; treating or reducing excessive daytime sleepiness;
  • insomnia hypersomnia; narcolepsy; interrupted sleep; sleep apnea; wakefulness; nocturnal myoclonus; REM sleep interruptions; jet-lag; shift workers' sleep disturbances; dyssomnias; night terror; insomnias associated with depression, emotional/mood disorders, as well as sleep walking and enuresis, and sleep disorders which accompany aging; Alzheimer's sundowning; conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules; conditions due to drugs which cause reductions in REM sleep as a side effect; syndromes which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep; and conditions which result from a diminished quality of sleep.
  • Pain disorders for which the compounds of the invention may be useful include neuropathic pain (such as postherpetic neuralgia, nerve injury, the "dynias", e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic mononeuropathy, painful polyneuropathy); central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system); postsurgical pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia); perioperative pain (general surgery, gynecological), chronic pain, dysmennorhea, as well as pain associated with angina, and inflammatory pain of varied origins (e.g.
  • osteoarthritis rheumatoid arthritis, rheumatic disease, teno- synovitis and gout
  • headache migraine and cluster headache, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization.
  • the subject compounds could further be of potential use in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
  • the dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the active ingredient may be administered to subjects (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
  • the dose will vary from subject to subject depending upon the nature and severity of disease, the subject's weight, special diets then being followed by a subject, concurrent medication, and other factors which those skilled in the art will recognize.
  • dosage levels of between 0.0001 to 10 mg/kg of body weight daily are administered to the subject, e.g., humans and elderly humans, to obtain effective modulation of M4 muscarinic acetylcholine receptors.
  • the dosage range will generally be about 0.5 mg to 1.0 g per subject per day which may be administered in single or multiple doses. In one embodiment, the dosage range will be about 0.5 mg to 500 mg per subject per day; in another embodiment about 0.5 mg to 200 mg per subject per day; and in yet another embodiment about 5 mg to 50 mg per subject per day.
  • Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient.
  • the pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient.
  • the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.
  • the compounds may be administered before bedtime. For example, the compounds may be administered about 1 hour prior to bedtime, about 30 minutes prior to bedtime or immediately before bedtime.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is contemplated.
  • the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules.
  • the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients
  • ingredients in addition to a compound of the present invention.
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is contemplated.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000: 1 to about 1 : 1000, such as about 200: 1 to about 1 :200.
  • Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • the subject compound may be employed in combination with other compounds which are known in the art, either administered separately or in the same pharmaceutical compositions, including, but are not limited to: anti-Alzheimer's agents; beta- secretase inhibitors, such as verubecestat; alpha 7 nicotinic agonists, such as ABT089, SSR180711 and MEM63908; HT2a modulators, such as pimavaserin; ADAM 10 ligands or activators; gamma- secretase inhibitors, such as LY450139 and TAK 070; gamma-secretase inhibitors; gamma secretase modulators; tau phosphorylation inhibitors; glycine transport inhibitors; LXR ⁇ agonists; ApoE
  • H12A11V1 anti-inflammatory compounds such as (R)-flurbiprofen, nitroflurbiprofen, ND-1251, VP-025, HT-0712 and EHT-202; PPAR gamma agonists, such as pioglitazone and rosiglitazone; CB-1 receptor antagonists or CB-1 receptor inverse agonists, such as AVE1625; antibiotics such as doxycycline and rifampin; CB-1 receptor antagonists or CB-1 receptor inverse agonists; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine, neramexane and EVT101; recombinant growth hormone; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H3 receptor antagonists such as ABT-834, ABT 829, GSK
  • butyrylchlolinesterase inhibitors such as donepezil (Aricept®, ( ⁇ )-2,3-dihydro-5,6-dimethoxy-2-[[l- (phenylmethyl)-4-piperidinyl]methyl]-l H -inden-l-one hydrochloride), tacrine, phenserine, ladostigil, ABT-089, galantamine (Razadyne®), and rivastigimine (Exelon®); N-methyl-D- aspartate receptor antagonists (e.g., Namenda® (memantine HC1, available from Forest
  • cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists
  • anti-inflammatory agents that can reduce neuroinflammation
  • glycogen synthase kinase beta inhibitors promoters of alpha secretase activity
  • PDE IV inhibitors including MEM1414, HT0712 and AVE8112
  • PDE-10 inhibitors PDE-10 inhibitors
  • Tau kinase inhibitors e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors
  • GSK3p inhibitors including AZD1080, SAR502250 and CEP16805
  • neuronal nicotinic agonists selective Ml agonists
  • HDAC inhibitors selective Ml agonists
  • Tau aggregation inhibitors e.g., Rember®
  • RAGE inhibitors e.g., TTP 488 (PF-4494700)
  • Simvastatin and/or cholesterol absorption inhibitors (such as Ezetimibe), or combinations of HMG- CoA reductase inhibitors and cholesterol absorption inhibitors (such as, for example, Vytorin®); fibrates (such as, for example, clofibrate, Clofibride, Etofibrate, and Aluminium Clofibrate);
  • nicotinic receptor agonists e.g., Simcor® (niacin/simvastatin, available from Abbott Laboratories, Inc.); LXR agonists; LRP mimics; H3 receptor antagonists; histone deacetylase inhibitors; hsp90 inhibitors; 5-HT4 agonists (e.g., PRX-03140 (Epix Pharmaceuticals)); 5-HT6 receptor antagonists; mGluRl receptor modulators or antagonists; mGluR5 receptor modulators or antagonists; mGluR2/3 antagonists; Prostaglandin EP2 receptor antagonists; PAI-1 inhibitors;
  • agents that can induce Abeta efflux such as gelsolin; Metal-protein attenuating compound (e.g, PBT2); and GPR3 modulators; and antihistamines such as Dimebolin (e.g., Dimebon®, Pfizer); or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention.
  • Abeta efflux such as gelsolin; Metal-protein attenuating compound (e.g, PBT2); and GPR3 modulators; and antihistamines such as Dimebolin (e.g., Dimebon®, Pfizer); or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention.
  • combinations of the compounds include combinations with agents for the treatment of schizophrenia, for example in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone,
  • the subject compound may be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, MDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole.
  • levodopa with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide
  • anticholinergics such as biperiden
  • the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
  • a pharmaceutically acceptable salt for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
  • the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent.
  • a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent Suitable examples of
  • phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine.
  • Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
  • An example of a dibenzazepine is clozapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other neuroleptic agents include loxapine, sulpiride and risperidone.
  • the neuroleptic agents when used in combination with the subject compound may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • a pharmaceutically acceptable salt for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixen
  • Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • the subject compound may be employed in combination with acetophenazine, alentemol, aripiprazole, amisuipride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, r
  • combinations of the compounds include combinations with agents for the treatment of pain, for example non-steroidal anti-inflammatory agents, such as aspirin, diclofenac, duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784; CB-2 agonists, such as 842166 and SAB378; VR-1 antagonists, such as AMG517, 705498, 782443, PAC20030, VI 14380 and A425619; bradykinin B 1 receptor antagonists, such as SSR240612 and NVPSAA164; sodium channel blockers and antagonists, such as VX409 and SPI860; nitric oxide synthase (
  • amantadine monoamine oxidase B15 (“MAO-B") inhibitors
  • MAO-B monoamine oxidase B15
  • 5HT receptor agonists or antagonists 5HT receptor agonists or antagonists
  • mGlu5 antagonists such as AZD9272
  • alpha agonists such as
  • AGNXX/YY neuronal nicotinic agonists, such as ABT894; NMDA receptor agonists or
  • AZD4282 selective serotonin reuptake inhibitors
  • SSNRI selective serotonin and norepinephrine reuptake inhibitors
  • duloxetine tricyclic antidepressant drugs, norepinephrine modulators; lithium; valproate; gabapentin;
  • pregabalin pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan.
  • the compounds of the present invention may be administered in combination with compounds useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, orexin antagonists, alpha- 1 antagonists, GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, orexin antagonists, orexin agonists, prokineticin agonists and antagonists,
  • compounds useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances including e.g., sedatives, hypnotics, anxi
  • pyrazolopyrimidines T-type calcium channel antagonists, triazolopyridines, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,
  • cyprazepam desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam, filorexant, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY- 156735, maprotiline, MDL- 100907, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methyprylon, midaflur, midazolam, modafini
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intraci sternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intraci sternal injection or infusion, subcutaneous injection, or implant
  • inhalation spray nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the subject or patient to whom the compounds of the present invention is administered is generally a human being, male or female, but may also encompass other mammals, such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates, for which treatment of the above noted disorders is desired.
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Oily suspensions may be formulated by suspending the active ingredient in a suitable oil. Oil-in-water emulsions may also be employed.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Pharmaceutical compositions of the present compounds may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • Pharmaceutical compositions of the present compounds in the form of a sterile injectable aqueous or oleagenous suspension may be formulated by known techniques for depo administration and thereby provide a sustained action over a longer period.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed.
  • the compounds of the present invention may also be formulated for administered by inhalation.
  • the compounds of the present invention may also be administered by a transdermal patch by methods known in the art.
  • DCM dichloromethane
  • DCE dichloroethane
  • DEA diethylamine
  • DEAD
  • mCPBA meta-chloroperbenzoic acid
  • MeOH methanol
  • MgS0 4 magnesium sulfate
  • Ms magnesium sulfate
  • the compounds of the present invention can be prepared in a variety of fashions.
  • the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • the following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
  • Step 1 benzyl tetrahydrofuran-3 -carboxylate
  • Step 2 benzyl 3 -methyltetrahydrofuran-3 -carboxylate
  • Step 1 methyl 4-methyltetrahydro-2H-pyran-4-carboxylate
  • reaction mixture was cooled to 0 °C, quenched with sat. H 4 C1 aqueous solution (30 mL) diluted with water (35 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (20 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as light yellow oil, which was moved forward without further purification.
  • Intermediate C is prepared from a commercially bromopyrazole C-l, which is borylated to provide boronic ester C-2. Protection of the pyrazole enables a Suzuki cross-coupling with a known iodide or bromide to yield product C-4. Deprotection provides intermediate C.
  • Step 1 4-(4.4.5.5-Tetramethyl-1.3.2-dioxaborolan-2-vn-lH-pyrazole
  • Step 2 fert-Butyl 4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate
  • Boc 2 0 (96 g, 0.48 mol) and DMAP (64 g, 0.64 mol) were added to a solution of 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole in DMF (1 L).
  • the reaction mixture was stirred at room temperature for 7 hours before the mixture was poured into water and EtOAc.
  • the organic layer was separated and washed with water and brine, and dried over anhydrous Na 2 S0 4 before concentrating to dryness.
  • the resulting residue was purified by silica gel column (10: 1 petroleum ethenEtOAc) to give the title compound.
  • Step 3 fert-Butyl 4-(2-chloropyridin-3-yl)-lH-pyrazole-l-carboxylate 2-Chloro-3-iodopyridine (100 g x 2, 0.42 mol) and tert-butyl 4-(2-chloropyridin-3-yl)-lH-pyrazole- 1-carboxylate (123 g, 0.42 mol) was dissolved in dioxane (2 L). The system was placed under N 2 and Pd(dppf)Cl 2 (15 g, 17 mmol) was added to the solution and the reaction was heated to 65 °C for 3 h. The reaction was cooled to RT and the mixture was poured into water and partitioned with EtO Ac. The organic was washed with water and brine, then dried over anhydrous Na 2 S0 4 before concentrating to dryness. The title compound was obtained and was used without further purification.
  • Step 2 6-chloro-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)picolinonitrile
  • the reaction mixture was stirred at room temperature for 16 hours to see complete conversion of the start material. It was worked up with water and EtOAc. The organic layer was collected and purified on a silica gel column, eluting with 40 % EtOAc in hexanes to get the desired product as a yellow solid.
  • Step 3 6-(imidazorL2-a1pyridin-7-yl)-5-(lH-pyrazol-4-yl)picolinonitrile hydrochloride
  • Oxidation with urea-hydrogen peroxide in the presence of trifluoroacetic anhydride provides N- oxide E-2. Subsequent o-methylation with dimethyl sulfite followed by Reissert-Kaufmann reaction with sodium cyanide affords intermediate E.
  • 2,4,6-trimethylbenzene-l-sulfonyl chloride (5 g, 22.9 mmol) was added to a solution of MTBE (50 mL) under nitrogen atmosphere at 0 °C, followed by the addition of tert-butyl hydroxycarbamate (3.0 g, 22.9 mmol) at 0 °C.
  • Et 3 N (3.2 mL, 22.9 mmol) was added dropwise to the reaction mixture, which was then was allowed to stir for 2 h.
  • the reaction product was filtered through sintered funnel and the filtrate was concentrated under vacuum up to 3 ⁇ 4 volume. Heptane (50 mL) was added to the concentrated filtrate, which was then stirred for 20 min wherein a precipitate formed.
  • Step 4 methyl 6-bromo-2-methylpyrazolo[L5-a "
  • Step 6 2-methyl-6-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyrazolorL5-a1
  • Intermediate K is prepared according to Scheme K via oxidation to arrive at N-oxide K-2 from a commercially available bromide K-1. Treating with POC13 provides intermediate K.
  • Intermediate L is prepared according to Scheme L via deprotonation to arrive at TMS protected pyridine L-2 from a commercially available 2,6-substituted pyridine L-1. Deprotonation again and treating with iodine provides L-3. Remove TMS provides intermediate L.
  • Step 1 6-chloro-2-(trifluoromethoxy)-3-(trimethylsilyl)pyridine
  • Step 1 methyl 5-bromo-6-chloro-3-fluoropicolinate
  • Step 1 (2-bromoethoxy)(tert-butyl)diphenylsilane
  • Intermediate O is prepared according to Scheme O via Seyferth-Gilbert homologation to arrive at terminal alkyne 0-2 from a commercially available aldehyde 0-1. Protection with TIPS provides intermediate O.
  • Step 1 3-bromo-2-chloro-6-ethynylpyridine
  • Step 2 3-bromo-2-chloro-6-((triisopropylsilyl)ethvnyl)pyridine
  • Step 1 3-(benzyloxy)-l-(hydroxymethyl)cyclobutanol
  • Step 2 3-(benzyloxy)-l-((4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-ylVlH-pyrazol-l- vDmethvDcyclobutanol
  • Step 3 l-((4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)methyl)cyclobutane- U-diol
  • Step 1 benzyl 2,2-dimethyl-3-oxobutanoate To a solution of compound benzyl 3-oxobutanoate (15 g, 78 mmol) in THF (100 mL) was added NaH (6.24 g, 156 mmol, 60%w) at 0 °C, the mixture was stirred at 0 °C for 30 min then iodomethane (22.15 g, 156 mmol) was added and the mixture was stirred for another 16 h. The reaction mixture was quenched with water (100 mL) then the mixture was extracted with Ethyl acetate (50 mL x 3).
  • Step 5 4-bromo-l-(3,3-difluoro-2,2-dimethylbutyl)-lH-pyrazole
  • 3-difluoro-2,2-dimethylbutan-l-ol 1.55 mmol
  • 4-bromo-lH- pyrazole 1.55 mmol
  • triphenylphosphine 3.98 g, 15.20 mmol
  • E-di-tert-butyl diazene-l,2-dicarboxylate 3.50 g, 15.20 mmol
  • the reaction mixture was concentrated and the residue was further purified by column chromatography (petroleum ether: Ethyl acetate 5: 1) to give the title compound as a yellow oil with aromatic smelling.
  • Step 6 l-(3.3-difluoro-2.2-dimethylbutvn-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-vn-lH- pyrazole
  • Step 1 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-l-ol
  • Step 3 tert-butyl(3,3-difluoro-2,2-dimethylpropoxy)diphenylsilane
  • Step 5 4-bromo-l-(3,3-difluoro-2,2-dimethylpropyl)-lH-pyrazole
  • Step 6 l-(3.3-difluoro-2.2-dimethylpropyn-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-vn-lH- pyrazole
  • Intermediate T is prepared according to Scheme T via opening epoxide to arrive at intermediate T from a commercially available pyrazol T-l .
  • Step 3 methyl- 1 -( 4-( 4.4.5.5-tetramethyl- 1.3.2-dioxaborolan-2-vQ- lH-pyrazol- 1 -vDbutan-2-ol
  • Step 1 benzyl 1-acetylcyclopropanecarboxylate
  • benzyl 3-oxobutanoate 5.0 g, 26.0 mmol
  • K 2 CO 3 9.0 g, 65.0 mmol
  • 1,2-dibromoethane 9.8 g, 52.0 mmol
  • the mixture was stirred at 60 °C for 16 h.
  • Step 2 benzyl 1-(1 J-difluoroethyDcyclopropanecarboxylate
  • Step 3 1-(1 J-difluoroethyOcyclopropanecarboxylic acid
  • Step 4 (l-(L l-difluoroethyl)cvclopropyl)methanol
  • Step 5 1 -((!-(! J-difluoroethyl)cvclopropyl)methyl)-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2- yl)-lH-pyrazole
  • Step 1 l-((3.3-difluorocvclobutvnmethvn-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-vn-lH- pyrazole
  • Step 1 methyl 7-bromoimidazorL2-a1pyridine-2-carboxylate
  • Compounds of formula (I) are prepared from reaction sequence that begins with reduction of a commercially ester 1-1 or intermediate A to alcohol 1-2. Alcohol 1-2 or known or commercially available (i.e., intermediate B is transformed to triflate or tosylate 1-3). Alkylation of pyrazole 1-5 (intermediate C) with electrophile 1-6, which is either 1-3 or a commercially available alkyl halide, in presence of the base provides adduct 1-7. Suzuki coupling of chloride 1-7 with a known or prepared boronic acid or ester (i.e., intermediate G or H) 1-8 provides compounds of the formula (I).
  • Compound (I) is prepared according to Scheme 16 via reduction by LiBH 4 to arrive at alcohol 16-2 from a commercially available ester 16-1.
  • a tosylation provides intermediate 16-3.
  • Alkylation of pyrazole 16-4 with electrophile 16-3, in presence of the base provides of the compound 16-5.
  • Deprotection of the 16-5 with TBAF provides compounds of the formula (I).
  • Suzuki coupling of commercially available or prepared chloride 15-1 with a known or prepared boronic acid or ester 15-2 provides the product 15-3.
  • Suzuki coupling of chloride 15-3 with a known or prepared boronic acid or ester 15-4 provides 15-5.
  • De-THP protection in presence of acid provides 15-6.
  • Alkylation of pyrazole 15-6 with electrophile 15-7, which is either prepared or a commercially available alkyl halide, in presence of the base provides 15-8.
  • Sandmeyer reaction of 15-8 provides compounds of the formula (I).
  • Compound 25-1 is prepared according to Example 9 and is treated with BS to produce 25-2. Bromide 25-2 is treated with dicyanozinc in presence of Pd catalyst to give 25-3. Suzuki coupling of chloride 25-3 with a known or prepared boronic acid or ester (i.e., intermediate G or H) 25-4 provides compounds of the formula (I).
  • Compounds of formula (I) are prepared by treating chlorides 27-1 with trimethylboroxine in presence of the Pd-catalyst and base.
  • Step 1 2-cyclopropyl-2,2-difluoroethan-l-ol
  • Step 2 2-cvclopropyl-2,2-difluoroethyl trifluoromethanesulfonate
  • 2-cyclopropyl-2,2-difluoroethanol 350 mg, 2.87 mmol
  • DCM dimethyl sulfoxide
  • Pyridine 0.927 ml, 11.46 mmol
  • trifiuoromethanesulfonic anhydride 968 ml, 5.73 mmol
  • Step 3 6-chloro-5-(l-(2-cyclopropyl-2,2-difluoroethyl)-lH-pyrazol-4-yl)picolinonitrile
  • Step 4 5-(l-(2-cvclopropyl-2,2-difluoroethyl)-lH-pyrazol-4-yl)-6-(imidazorL2-a1pyridin-7- yPpicolinonitrile
  • Step 1 6-chloro-5-(l-((l-methylcyclopropyl)methyl)-lH-pyrazol-4-yl)picolinonitrile
  • DIAD (0.950 ml, 4.89 mmol) was added to a mixture of 6-chloro-5-(lH-pyrazol-4-yl)picolinonitrile (1000 mg, 4.89 mmol), triphenylphosphine (1282 mg, 4.89 mmol), (l-methylcyclopropyl)methanol (842 mg, 9.77 mmol) in Toluene (20 ml) atO °C. The mixture was stirred for two days at room temperature. The mixture was concentrated and worked up; LC-MS shows product formation.
  • Example 5 The following example in Table 3 was prepared according to Scheme 3 using the procedure outlined in the synthesis of Example 50.
  • Stepl (l-(trifluoromethyl)cyclopropyl)methanol was prepared accoding procedure Example 1 stepl .
  • Step 2 4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-l-((l-(trifluoromethyl)cvclopropyl)- methyl)- lH-pyrazole
  • Step 3 6-chloro-5-(l-((l-(trifluoromethyl)cyclopropyl)methyl)-lH-pyrazol-4-yl)picolinonitrile 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-((l-(trifluoromethyl)cyclopropyl)methyl)-lH- pyrazole (0.77 g, 1.291 mmol), 5-bromo-6-chloropicolinonitrile (0.281 g, 1.291 mmol), Pd(dppf)Cl 2 dichloromethane complex (0.105 g, 0.129 mmol) and potassium carbonate (0.535 g, 3.87 mmol) were charged in a reaction vessel with Dioxane (10 ml) and Water (1 ml).
  • a microwave vial containing chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-l, -biphenyl)[2- (2-aminoethyl)phenyl] palladium(ii) methyl-t-butyl ether adduct (1 1.39 mg, 0.014 mmol), 2-methyl- 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoindolin-l-one (83 mg, 0.303 mmol), and 6-chloro- 5-(l-((l-(trifluoromethyl)cyclopropyl)methyl)-lH-pyrazol-4-yl)picolinonitrile (90 mg, 0.275 mmol) was sealed and purged with nitrogen and THF (1837 ⁇ ) was added, purging continued for 30 min after K3P04 (551 ⁇ , 0.551 mmol) was added.
  • Step 1 7-(3-chloro-5,6-difluoropyridin-2-yl)imidazorL2-a1pyridine
  • Step 2 7-(5,6-difluoro-3-(l-((l-(trifluoromethyl)cvclopropyl)methyl)-lH-pyrazol-4-yl)pyridin-2- yl)imidazo
  • pyridine 7-(5,6-difluoro-3-(l-((l-(trifluoromethyl)cvclopropyl)methyl)-lH-pyrazol-4-yl)pyridin-2- yl)imidazo
  • Step 1 l-neopentyl-4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)-lH-pyrazole
  • Step 3 6-(2-methyl-[L2,41triazolo[L5-alpyridin-7-yl)-5-(l-neopentyl-lH-pyrazol-4- vDpicolinonitrile
  • Step 3 3-(l-isopentyl-lH-pyrazol-4-yl)-2-(3-oxoisoindolin-5-yl)pyridine 1-oxide
  • Step 4 6-(6-chloro-3-(l-isopentyl-lH-pyrazol-4-yl)pyridin-2-yl)isoindolin-l-one
  • Step 1 methyl 5-(3-(l-isopentyl-lH-pyrazol-4-yl)pyridin-2-yl)-2-methylbenzoate
  • 2-chloro-3-(l-isopentyl-lH-pyrazol-4-yl)pyridine 5.0 g, 20.02 mmol
  • 3-(methoxycarbonyl)-4-methylphenyl)boronic acid 7.77 g, 40.0 mmol
  • 1, 1'- bis(di-tert-butylphosphino)ferrocene palladium di chloride 100 mg, 0.153 mmol.
  • Step 2 3-(l-isopentyl-lH-pyrazol-4-yl)-2-(3-(methoxycarbonyl)-4-methylphenyl)pyridine 1-oxide
  • a solution of methyl 5-(3-(l-isopentyl-lH-pyrazol-4-yl)pyridin-2-yl)-2-methylbenzoate (3.60 g,
  • Step 3 methyl 5-(6-chloro-3-(l-isopentyl-lH-pyrazol-4-yl)pyridin-2-yl)-2-methylbenzoate
  • Step 4 methyl 2-(bromomethyl)-5-(6-chloro-3-(l-isopentyl-lH-pyrazol-4-yl)pyridin-2-yl)benzoate
  • methyl 5-(6-chloro-3-(l-isopentyl-lH-pyrazol-4-yl)pyridin- 2-yl)-2-methylbenzoate 280.0 mg, 0.704 mmol
  • N-bromosuccinimide 250.0 mg, 1.407 mmol
  • benzoyl peroxide 85.0 mg, 0.352 mmol.
  • Carbon tetrachloride (7.04 mL) was added, the vial sealed, and the reaction heated to 90° C on a hotplate for 30 minutes.
  • the sample was cooled, washed with saturated sodium bicarbonate, and the organic layer dried over sodium sulfate.
  • the sample was filter and concentrated to provide the title compound that was used without further purification.
  • Step 5 6-chloro-3-(l-isopentyl-lH-pyrazol-4-yl)-2-(3-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5- yl)pyridin-l-ium
  • Step 1 5-(l-((l-hydroxycyclobutyl)methyl)-lH-pyrazol-4-yl)-6-(2-methylimidazo
  • Step 2 5-( 1 -(( 1 -fluorocvclobutynmethyl)- lH-pyrazol-4-vn-6-(2-methylimidazor 1.2-al
  • Step 1 5-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)-6-(imidazo[L2-alpyridine-7- vDpicolinonitrile
  • Stepl 2-chloro-3-(l-neopentyl-lH-pyrazol-4-yl)-6-((triisopropylsilyl)ethynyl)pyridine
  • Step 2 2-methyl-7-(3-(l-neopentyl-lH-pyrazol-4-yl)-6-((triisopropylsilyl)ethynyl)pyridin-2- vPimidazolO-alpyridine
  • Step 3 2-methyl-7-(3-(l-neopentyl-lH-pyrazol-4-yl)-6-((triisopropylsilyl)ethvnyl) pyridin-2- yl)imidazo
  • Step 2 5-(l-(2-cyclopropyl-2-hydroxy ethyl)- lH-pyrazol-4-yl)-6-(imidazo
  • Step 3 5-(l-(2-cvclopropyl-2-fluoroethyl)-lH-pyrazol-4-yl)-6-(imidazorL2-a1 pyridin-7- yPpicolinonitrile
  • Step 1 6-chloro-5-(l-(2-oxopropyl)-lH-pyrazol-4-yl)picolinonitrile
  • Step 2 6-chloro-5-(l-(3,3,3-trifluoro-2-hvdroxy-2-methylpropyl)-lH-pyrazol-4-yl)picolinonitrile
  • Step3 6-(2-methylimidazorL2-a1pyridin-7-yl)-5-(l-(3,3,3-trifluoro-2-hvdroxy-2-methylpropyl)-lH- pyrazol-4-yl)picolinonitrile
  • Step 1 (E)-6-(2-methylimidazorL2-a1pyridin-7-yl)-5-(l-(3 ,3 ,3-trifluoro-2-methylprop-l-en-l-yl)- lH-pyrazol-4-yl)picolinonitrile (Scheme 15).
  • Step 2 6-(2-methylimidazo rL2-a1pyridin-7-yl)-5-(l-(3,3,3-trifluoro-2-methylpropyl)-lH-pyrazol-
  • Step 1 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-l-ol
  • Step 3 5-(l-(3-((tert-butyldiphenylsilvnoxy)-2.2-dimethylpropyn-lH-pyrazol-4-vn-6-(2- methylimidazor 1 ,2-alpyridin-7-yl)picolinonitrile
  • Step 4 5-(l-(3-hydroxy-2,2-dimethylpropyl)-lH-pyrazol-4-yl)-6-(2-methylimidazo[L2-alpyridin-7- vDpicolinonitrile
  • Stepl 6-chloro-5-(l-((L3-dihvdroxycvclobutyl)methyl)-lH-pyrazol-4-yl)picolinonitrile
  • Step 2 5-(l -(( 1.3 -dihydroxycvclobutynmethyl lH-pyrazol-4-yl)-6-( 1.2-dimethyl - 1H- benzo[dlimidazol-5-yl)picolinonitrile
  • Step3 5-( 1 -((( 1 s.3 s)- 1.3 -difluorocvclobutynmethyl)- lH-pyrazol-4-yl)-6-(l .2-dimethyl- ⁇ H- benzord1imidazol-5-yl)picolinonitrile
  • Step 1 5-(l-(((lr,3r)-3-(benzyloxy)-l-hvdroxycvclobutyl)methyl)-lH-pyrazol-4-yl)-6- chloropicolinonitrile
  • (lr,3r)-3-(benzyloxy)-l-((4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)methyl)cyclobutanol (Intermediate Q) (250 mg, 0.651 mmol),
  • Step 3 5-0 -((( ⁇ s3 s)-3 -(benzyloxy)- 1 -fluorocvclobutvOmethyn- lH-pyrazol-4-yl)-
  • Step 4 6-(1.2-dimethyl-lH-benzordlimidazol-5-vn-5-(l-(((ls.3s)-l-fluoro-3- hvdroxycvclobutyl)methyl)-lH-pyrazol-4-yl)picolinonitrile
  • Step 5 5-(l-(((lr r)-l -difluorocvclobutyl)metfayl)-lH-pyrazol-4-yl)-6-(1.2- dimethyl-lH-benzord1imidazol-5-yl)picolinonitrile
  • Step 1 (ls,3s)-3-(benzyloxy)-l-((4-(2-chloropyridin-3-yl)-lH-pyrazol-l-yl)methyl)cvclobutanol
  • Step 2 (ls.3s)-3-(benzyloxy)-l-((4-(2-(2-methyl-ri.2.41triazolori.5-alpyridin-7-yl)pyridin-3-yl)- lH-pyrazol- 1 -yl)methyl)cvclobutanol
  • Step 3 7-(3 -( 1 -((( 1 r,3 r)-3 -(benzyloxy)- 1 -fluorocyclobutvPm ethyl)- 1 H-pyrazol-4-yl)
  • Step 4 (lr.3rV3-fluoro-3-((4-(2-(2-methyl-rL2.41triazolori.5-alpyridin-7-vnpyridin- 3 -vP- lH-pyrazol- 1 -vDmethyDcyclobutanol
  • Step 5 3-fluoro-3-((4-(2-(2-methyl L2.41triazolori.5-alpyridin-7-vPpyridin-3-vP-lH-pyrazol-l- yPmethyPcyclobutanone
  • Step 1 (6-chloro-3-fluoro-5-(l-(tetrahvdro-2H-pyran-2-yl)-lH-pyrazol-4-yl)pyridine- 2-vDmethanol
  • Step 4 (6-(1.2-dimethyl-lH-benzord1imidazol-5-vn-3-fluoro-5-(l-(tetrahvdro-2H- pyran-2-vD-lH-pyrazol-4-vDpyridin-2-yl)methanol
  • Step 5 5-(5-fluoro-6-methyl-3-(lH-pyrazol-4-yl)pyridin-2-yl)-L2-dimethyl-lH-benzo

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Abstract

La présente invention concerne des composés de type pyrazol-4-yl-pyridine qui sont des modulateurs allostériques du récepteur muscarinique M4 de l'acétylcholine. La présente invention concerne également des utilisations des composés décrits dans la présente description dans le traitement ou la prévention potentiels de troubles et maladies neurologiques et psychiatriques dans lesquels sont impliqués les récepteurs muscariniques M4 de l'acétylcholine. La présente invention concerne également des compositions comprenant ces composés. La présente invention concerne également des utilisations de ces compositions dans la prévention ou le traitement potentiels de telles maladies dans lesquelles sont impliqués les récepteurs muscariniques M4 de l'acétylcholine.
PCT/US2018/038891 2017-06-27 2018-06-22 Modulateurs allostériques de type 3-(1h-pyrazol-4-yl)pyridine du récepteur muscarinique m4 de l'acétylcholine Ceased WO2019005588A1 (fr)

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WO2019000238A1 (fr) 2017-06-27 2019-01-03 Merck Sharp & Dohme Corp. Modulateurs allostériques de 5-(pyridin-3-yl)oxazole du récepteur muscarinique m4 de l'acétylcholine
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US11339156B2 (en) 2022-05-24
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EP3644991A4 (fr) 2021-03-24
US20210380580A1 (en) 2021-12-09
WO2019000237A1 (fr) 2019-01-03

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